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New genetic approaches in understanding susceptibility for metabolic syndrome in

Mediterranean populations

(FP7-279171-1)

2012 - 2015

DIABESITY - A WORLD WIDE CHALLANGE

9-10 February 2012 - Brussels

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MEDIGENE Objectives

Finality: improve genetic markers (clinical scale); better explain heritability; offer a new basis for personalized medicine

Insulin resistance syndrome - metabolic syndrome (MetS) in immigrant populations in Europe (host and home countries)

Unravel new susceptibility genes for MetS considering the genetic variability (stratification) in case-control Genome Wide Association Studies (GWAS) and gene environment interaction

Consortium of 13 countries in the Mediterranean area : clinical endocrinologists, geneticists, anthropologists and archeologists

Obesity gene

GWAS

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1.2% 17-20 % 40 %

Modern migrations (immigration)

Host Total % Composition

France 6,471,000 10.18 Algeria, Morocco, China

Spain 4,790,000 10.79 Romania, Morocco, Bolivia

Italy 2,519,000 4.28 Romania, Albania, Ukraine

Greece 974,000 8.66 Albania, Bulgaria, Romania

Specificity of MEDIGENE Visceral obesity, hyperlipidemia, hypertension and diabetes

International Diabetes Federation (IDF)

Questionable candidate for GWAS (heterogeneous)

Insulin resistance - unique feature (fundamental biological process)

MetS correlated with health indices in population (CV mortality)

Vulnerable, health status (assistance), low income

9% of world population, 8% of European community

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Relationship between migration and Health

Genetic

background ?

Home

1st

GEN Host

(NATIVES) Salmon

theory

Selection

theory

Statistically

immortal

Contact

2nd

GEN

Vulnerable

populations

Epidemiological

paradoxes Age of

migration

Refugee Acculturation

Life style Stress

Modern, historical and ancestral migration

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Modern migrations (Immigrants)

Albanese (Illyrians ),

Turkish (Altaic populations

with Central Asians

components), Romanian

(Geto-Thracic populations

from the Carpato-Danubian

basin), North African

immigrants (Berbers

admixed with Bedouin tribes

or Canaanite-Phoenicians in

historical times) - Algerians,

Tunisians and Moroccans.

MEDIGENE

populations

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Historical migrations in Mediterranean

Antiques Romans

(IV-I Century AD)

(n = 3800)

Phoenicians

Black Sea

Atlantic

Ocean

Maures

Numidians

Libyans

Ligurians

Celts

Traces

Scythians

Massalia

Hemeroscopion

Neapolis

Mylai

Alalia

Malaca Hippone

Sulcis

Utique Carthage

Leptis

Magna Egyptians

TYR

Apollonia

Thera

Kourion

Salamine

Sinope

Kimmericon

Pontus

euxinus

Ionians

Tarragona

Romans

Dorians

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Capsian culture

Franco- Cantabrian

Refugia

Carpato- Danubian

basin

Indo-Europeans

Aterian culture

40 kya

40 kya

40 kya

20 kya 20 kya

Azilian culture

North Africa

Europe

Black Sea

Atlantic Ocean

Archeo-genetics of Europe (Paleolithic)

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Haplotyping approach in MEDIGENE mutation

Genetic drift

Evolution

Admixture

Natural selection

Haplotypes

Haplotype 1 Haplotype 2

Haplotype 3 Haplotype 4 Haplotype 5

Ancestral haplotype

Recombination

Linkage disequilibrium

SNP

c t g g c t t a g c c a t a c c

a

t

g

a

g

c

t

t

c

a

g

Unphased DNA

Phased DNA

Classical GWAS

(“frequentist”)

112

h14 h15

h4

h11

h5

h7

h1

h2

h9

h10

111

112 221

211

121

122 112

121 111

Phylogeny

Rare SNP

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Working packages

WP1 1st STAGE

GWAS

600 000 SNPs

• • • • • • • • • • • • • •

140

genes

mtDNA

Y Chr

13 000 SNP

WP2 Ancient DNA study

In historical Romans

Ancient DNA Available DNA

WP3 Locus refining WP4 1st STAGE analysis

CC association in

host countries

WP8 Replication in

Home countries

Rare SNPs

[mutation]

Replication

Filtered

SNPs

WP5 Epidemiology in host and home countries &

novel recruitment for G x E interaction

WP6 2nd STAGE - Replication

Genotyping with filtered SNPs

WP7 2nd stage analysis

and meta-analysis

New DNA sampling

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Methods of MEDIGENE

Next Generation Sequencing

BC-platforms

Design of 600 000 SNP + 13 000 customized SNP

GeneTitan (Barcelona)

Mirrored

Barcelona Montpellier

Genome Wide Association studies

Replication

Data integration

Bioinformatics & statistics

GS Junior (Montpellier) FLX 454

Discovery

AXIOM Chip Primary analysis

Secondary analysis

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Expected results

New genes or allelic variants specific to populations - may help diagnosis, treatment and predictive actions

Alternative for classical GWAS - considering rare variants (SNP) - ethnic specific and explaining better association (OR) and heritability in population

Explain a series of epidemiological paradoxes - e.g. lower mortality in immigrants from Maghreb in France (men but not women) - differences in MetS between North and South in France - low CV mortality in Greeks at the first generation - role of the Mediterranean diet

Alternative explanation of insulin resistance - energy allocation mechanism versus adaptation of humans in relation with fertility, population density, social competitiveness, rural to urban transition

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Consortium Florin Grigorescu (CO), Michel Pugeat (France), Ramon Gomis, Josep M. Macias (Spain), Mihai Coculescu (Romania), Renato Pasquali, Giorgio Sesti, Vincenzo Trischitta, Davide Lauro (Italy), Agathocles Tsatsoulis (Greece), Elza Khusnutdinova (Russia), Sonia Abdelhak (Tunisia), Akila Zenati (Algeria), Abdelhamid Barakat (Morocco), IIly Agron (Albania), Timo Kanninen (Finland), Robert Hermann (Hungary), Ilhan Satman (Turkey)

Nathalie VERCUYSSE

Clelia CASALINO

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Human genetic diversity is a source of persistence and increase in the

differences in health seen in various EU citizens disadvantaged by inequalities and low-income. Understanding and accepting human genetic diversity, in opposition

to biological egalitarism represents a major advance in current thinking and a positive attitude. Group differences will help t o understand how genetic and environmental factors produce biological outcomes. We should bear in

mind that genetic diversity is a virtue of mankind not a defect, and a source of evolutionary resilience and adaptation assuring survival and health with potential

positive economic consequences on agriculture and environment.

Understanding the way of life of different people in native countries, consideration of their way of life, natural (ancestral) ecological niche, consequences of migration in a broader perspective as a potential factor of global increase in prevalence of diabetes/obesity, impact of deregulation of food supplies in modern times.

Perspectives and ethical considerations